Lung-protective effects of the metalloporphyrinic peroxynitrite decomposition catalyst WW-85 in interleukin-2 induced toxicity.
Recombinant interleukin-2 (IL-2) therapy for malignancy is associated with a pulmonary vascular leakage syndrome (VLS) similar to that seen in sepsis. We investigated the possibility that the IL-2-induced VLS may be associated with the release of peroxynitrite (ONOO(-)), and used a model of IL-2-induced VLS in sheep to test the effects of the ONOO(-) decomposition catalyst WW-85. Eighteen sheep were chronically instrumented and randomly divided into three groups (n=6 per group): sham: lactated Ringer's solution, control: IL-2, and treatment: IL-2 and WW-85. Treatment with WW-85 significantly improved lung transvascular fluid flux, decreased lipid peroxidation, limited iNOS as well as PAR intensity, prevented tachycardia, and attenuated the increase in core body temperature resulting from IL-2 treatment. These findings suggest that ONOO(-) plays a pivotal role in the pathology of IL-2-induced pulmonary VLS, and that WW-85 may become a useful treatment option.
Maybauer
Dirk M
DM
Department of Anesthesiology, Investigational Intensive Care Unit, The University of Texas Medical Branch and Shriners Burns Hospital for Children at Galveston, 301 University Blvd., Galveston, TX 77555-0833, USA.
Maybauer
Marc O
MO
Szabó
Csaba
C
Westphal
Martin
M
Traber
Lillian D
LD
Enkhbaatar
Perenlei
P
Murthy
Kanneganti G K
KG
Nakano
Yoshimitsu
Y
Salzman
Andrew L
AL
Herndon
David N
DN
Traber
Daniel L
DL
D000818:Animals; D019559:Capillary Leak Syndrome / Q000139:chemically induced / Q000517:prevention & control*; D002199:Capillary Permeability / Q000187:drug effects*; D002384:Catalysis; D006439:Hemodynamics / Q000187:drug effects; D007376:Interleukin-2 / Q000009:adverse effects* / Q000627:therapeutic use; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D008196:Lymph; D008315:Malondialdehyde / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D009569:Nitric Oxide / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D011659:Pulmonary Gas Exchange; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012756:Sheep; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D007376:Interleukin-2; D011994:Recombinant Proteins; C506898:WW85 compound; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II